Establishing Levoketoconazole-Specific Benefits in Cushing Syndrome

Following results from the SONICS trial, which showed levoketoconazole was effective in endogenous Cushing syndrome, researchers designed the LOGICS study to evaluate drug-specific cortisol normalization. According to the authors, treatment with levoketoconazole induced frequent normalization of mean urinary-free cortisol (mUFC) and improvements in patients’ lipid profiles. The data were reported in Pituitary.

The phase 3 placebo-controlled LOGICS study enrolled 79 patients to titration-maintenance for 14 to 19 weeks with levoketoconazole, followed by randomized withdrawal and restoration phases of approximately 8 weeks each. The primary end point was loss of response, defined as mUFC >1.5 × upper limit of normal.

A total of 39 patients who held a stable titration-maintenance dose for 4 weeks or more—plus 5 patients who completed the SONICS trial—were randomized to levoketoconazole (n=22) or placebo (n=22). During the withdrawal phase, 21 (95.5%) patients on placebo lost mUFC response compared with 9 (40.9%) patients who continued levoketoconazole (–54.5%; 95% CI, –75.7 to –27.4; P=.0002).

After the withdrawal phase, 11 (50.0%) levoketoconazole patients achieved mUFC normalization compared with 1 (4.5%) placebo patient (45.5%; 95% CI, 19.2-67.9; P=.0015). The authors noted restarting levoketoconazole reversed loss of cortisol control in most placebo patients.

Adverse events were observed in 89% of levoketoconazole patients, with the most common events being nausea (29%) and hypokalemia (26%). Additional adverse events of interest included liver-related events (10.7%), QT interval prolongation (10.7%), and adrenal insufficiency (9.5%).

Limitations of the study included the short withdrawal phase, and the authors noted that several patients in the placebo group required early rescue treatment. They also acknowledged the presence of baseline differences between the groups, though they stated these differences did not meaningfully affect interpretation of the data.

Overall, the study’s authors attributed treatment benefits to levoketoconazole given the “loss of benefit upon withdrawal to placebo and restoration upon reintroduction of active therapy.” They supported the use of levoketoconazole in patients with endogenous Cushing syndrome.